Causal Associations of Adiposity and Body Fat Distribution With Coronary Heart Disease, Stroke Subtypes, and Type 2 Diabetes Mellitus: A Mendelian Randomization Analysis

Caroline E Dale, Ghazaleh Fatemifar, Tom M Palmer, Jon White, David Prieto-Merino, Delilah Zabaneh, Jorgen E L Engmann, Tina Shah, Andrew Wong, Helen R Warren, Stela McLachlan, Stella Trompet, Max Moldovan, Richard W Morris, Reecha Sofat, Meena Kumari, Elina Hyppönen, Barbara J Jefferis, Tom Gaunt, Yoav Ben-ShlomoAng Zhou, Aleksandra Gentry-Maharaj, Andy Ryan, UCLEB Consortium, METASTROKE consortium, Renée de Mutsert, Raymond Noordam, Mark J Caulfield, J Wouter Jukema, Bradford Worrall, Patricia B Munroe, Usha Menon, Chris Power, Diana J L Kuh, Debbie A Lawlor, Steve E Humphries, Dennis O Mook-Kanamori, George Davey Smith, Naveed Sattar, Mika J Kivimaki, Jacqueline F Price, Frank Dudridge, Aroon Hingorani, Michael V Holmes, Juan P Cass

Research output: Contribution to journalArticle (Academic Journal)peer-review

230 Citations (Scopus)
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Background: Implications of different adiposity measures on cardiovascular disease aetiology remain unclear. In this paper we quantify and contrast causal associations of central adiposity (waist:hip ratio adjusted for BMI (WHRadjBMI)) and general adiposity (body mass index (BMI)) with cardiometabolic disease.

Methods: 97 independent single nucleotide polymorphisms (SNPs) for BMI and 49 SNPs for WHRadjBMI were used to conduct Mendelian randomization analyses in 14 prospective studies supplemented with CHD data from CARDIoGRAMplusC4D (combined total 66,842 cases), stroke from METASTROKE (12,389 ischaemic stroke cases), type 2 diabetes (T2D) from DIAGRAM (34,840 cases), and lipids from GLGC (213,500 participants) consortia. Primary outcomes were CHD, T2D, and major stroke subtypes; secondary analyses included 18 cardiometabolic traits.

Results: Each one standard deviation (SD) higher WHRadjBMI (1SD~0.08 units) associated with a 48% excess risk of CHD (odds ratio [OR] for CHD: 1.48; 95%CI: 1.28-1.71), similar to findings for BMI (1SD~4.6kg/m2; OR for CHD: 1.36; 95%CI: 1.22-1.52). Only WHRadjBMI increased risk of ischaemic stroke (OR 1.32; 95%CI 1.03-1.70). For T2D we find OR 1.82 (95%CI 1.38-2.42) per 1SD WHRadjBMI and OR 1.98 (95%CI 1.41-2.78) per 1SD BMI. Both WHRadjBMI and BMI were associated with increased left ventricular hypertrophy, glycaemic traits, interleukin-6, and circulating lipids. WHRadjBMI was associated with carotid intima-media thickness (37%; 95%CI: 7%-74% per 1SD).

Conclusions: Both general and central adiposity have causal effects on CHD and T2D. Central adiposity may have a stronger effect on stroke risk. Future estimates of adiposity burden on health should include measures of central and general adiposity.
Original languageEnglish
Pages (from-to)2373-2388
Number of pages16
Issue number24
Early online date12 May 2017
Publication statusPublished - 13 Jun 2017

Structured keywords

  • Bristol Population Health Science Institute


  • adiposity
  • body fat distribution
  • body mass index
  • coronary artery disease
  • Mendelian randomization analysis
  • stroke
  • waist-hip ratio


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